2-arylindole derivatives as npges-i inhibitors

ABSTRACT

A 2-arylindole compound substituted in position 5, of formula (I): in which X, Y, Z, W, A, R and R′ have the meanings given in the description, a pharmaceutical composition comprising it, and also intermediate compounds and a preparation process therefor.

The present invention relates to a 2-arylindole compound substituted inposition 5, to a pharmaceutical composition comprising it, tointermediate compounds and to a preparation process therefor.

More particularly, the present invention relates to a 2-arylindolecompound substituted in position 5, which has inhibitory activity onmPGEs-1.

It is known that prostaglandins (PG) are oxygenated fatty acidssynthesized and released into the extracellular space, and then into theplasma, urine and other biological fluids.

They are important bioregulators, but also inflammation mediators thatmodulate intracellular reactions and intercellular communication.

The prostaglandins E₂ (PGE₂) have an important physiological role ofregulating renal function, vascular homeostasis, bone remodelling,induction of fever, gastrointestinal function and pregnancy. Besidesthese physiological functions, the PGE₂ prostaglandins behave as potentmediators of acute inflammation (inducing hyperalgesia, vasodilatationand discharge of fluids from vessels: Vane J. R. and Botting R. M. 1997“Anti-inflammatory drugs and their mechanism of action” Inflamm. Res. 47(2): p. 78) and chronic inflammation. Specifically, the PGE₂prostaglandins are particularly abundant in articular inflammatorypathologies. PGE₂ prostaglandins also play a role in pain and are potentpyretic agents (Ayoub S. S. et al., 2004 “A ceta-minophen-inducedhypothermia in mice is mediated by a prostaglandin endoperoxide synthase1 gene-derived protein”, PNAS 101: 11165-11169; Ivanov A. et al. 2002“Prostaglandin E₂—synthesizing enzymes in fever: differentialtranscriptional regulation”, Am. J. Physiol. Regul. Integr. Comp.Physiol. 283: R1104-R1117).

The enzyme responsible for the synthesis of PGE₂ prostaglandins isprostaglandin E synthase (PGES), which converts the endoperoxide PGH₂,formed from arachidonic acid by the action of cyclooxygenases, intoPGE₂. The activity of PGES has been found both in the cytosolic fractionand membrane-bound in various types of cells.

Three enzymatic forms have been identified (Kudo I. et al. 2005“Prostaglandin E synthase, a terminal enzyme for prostaglandin E₂biosynthesis”, Journal of Biochemistry and Molecular Biology 38,633-638); among these, microsomial PGES-1 (mPGES-1) is a membrane-boundenzyme that requires glutathione as an essential cofactor for itsactivity.

The expression of mPGES-1 is induced by pro-inflammatory stimuli such asIL-1β or LPS (Proc. Natl. Acad. Sci. 96: 7220, 1999). It is co-localizedtogether with COX-2 on the endoplasmatic reticum and on the nuclearenvelope (Lazarus M. et al. 2002 “Biochemical characterization of mousemicrosomal prostaglandin E synthase-1 and its colocalization withcyclooxygenase-2 in peritoneal macrophages” Arch. Biochem. Biophys. 397:336; Murakami M. et al. 2000 “Regulation of prostaglandin E2biosynthesis by inducible membrane-associated prostaglandin E2 synthasethat acts in concert with cyclooxygenase-2” J. Biol. Chem. 275: 32783;Yamagata K. et al. 2001 “Coexpression of microsomal-type prostaglandin Esynthase with cyclooxygenase-2 in brain endothelial cells of rats duringendotoxin-induced fever” J. Neurosci. 15; 21(8): 2669-77). Although thetwo enzymes (COX-2 and mPGES-1) have a functional connection andco-expression, their rate of induction differs in a few cellularsystems, indicating different regulatory induction mechanisms (J.Immunol. 167: 469, 2001).

Drugs that inhibit the enzyme COX-2 have been shown to be effective inalleviating inflammation and pain in chronic inflammatory pathologiessuch as arthritis, but their prolonged use may induce tissue damagecaused by an overproduction of cytokines, for instance TNFα and IL-1β(Stichtenoth D. O. 2001 “Microsomal prostaglandin E synthase isregulated by proinflammatory cytokines and glucocorticoids in primaryrheumatoid synovial cells” J. Immunol. 167: 469). In addition, theprolonged use of these drugs is associated with cardiovascular sideeffects. This has led to the withdrawal from the market of a number ofselective COX-2 inhibitors and to a revision of the indications for theentire class of these drugs.

Recent research efforts are directed towards overcoming the side effectsof COX-2 inhibitors by studying mPGES-1 inhibitors for the purpose ofdeveloping drugs that are active in the treatment of inflammation andpain.

In addition, numerous studies have demonstrated that the PGE₂prostaglandins are tumour-promoting factors (Castellone M. D. et al.2005 “Prostaglandin E₂ promotes colon cancer growth through a novelGs-Axin-B-catenin”, Science 310, 1504-1510; Mehrotra S., et al. 2006“Microsomal prostaglandin E₂ in breast cancer: a potential target fortherapy”, J. Pathol. 208(3): 356-63; Nakano et al. 2006 “Induction ofmacrophagic prostaglandin E2 synthesis by glioma cells”

J. Neurosurgery 104(4), 574-582) that are involved in angiogenesis, cellproliferation and cell migration functions. Selective FANS and COX-2inhibitors are also found to inhibit various types of tumours, includingcolorectal, oesophageal, breast, lung and bladder tumours by means ofinhibiting PGE₂. PGE₂ prostaglandins derived from COX-2 induce tumourgrowth by means of binding to the actual receptors and activatingsignals for controlling cell proliferation, migration, apoptosis andangiogenesis (Wang D. et al. 2006 “Prostaglandin and cancer” Gut. 55(1):115-22; Han C. et al. 2006 “Prostaglandin E₂ receptor EP1transactivates EGFR/MET receptor tyrosine kinases and enhancesinvasiveness in human hepatocellular carcinoma cells”, Journal ofCellular Physiology 207: 261-270).

A 2-arylindole compound substituted in position 5 that has selectiveinhibitory activity on mPGES-1 has now been found.

In a first aspect, the present invention relates to a 2-arylindolecompound substituted in position 5, of formula (I):

in which:

-   -   X is a halogen atom or a (C₁-C₃)alkyl, trifluoromethyl, nitro,        amino, cyano, di(C₁-C₃)alkylamino, hydroxy, (C₁-C₃)alkoxy,        phenyl or (C₁-C₃)alkylphenyl group;    -   Y and Z, which may be identical or different, are an H or        halogen atom, or a (C₁-C₃)alkyl, trifluoromethyl, nitro, amino,        di(C₁-C₃)alkylamino, hydroxy, (C₁-C₃)alkoxy, phenyl, COOH,        (C₁-C₃)alkyl-COOH, (C₂-C₃)alkenyl-COOH, COOR, CONH₂, SO₂CH₃,        SO₂NHCH₃ or NHSO₂CH₃ group;    -   W is an O atom or a CH₂ or NH group;    -   R is a hydrogen atom or a (C₁-C₆)alkyl or (C₃-C₇)cycloalkyl        group optionally substituted with 1 to 3 hydroxy groups;    -   R′ is an H atom or a (C₁-C₆)alkyl or (C₃-C₇)cycloalkyl group        optionally substituted with 1 to 3 hydroxy groups;    -   A is a phenyl, naphthyl or pyridine group optionally substituted        with 1 to 3 substituents, which may be identical or different,        chosen from halogen, (C₁-C₆)alkyl optionally substituted with 1        to 3 hydroxy groups, trifluoromethyl, nitro, amino,        di(C₁-C₃)alkylamino, hydroxy, (C₁-C₃)alkoxy, benzyloxy, COOH,        COOR, SO₂CH₃, SO₂NHCH₃, NHSO₂CH₃, POR₁R₂, OPOR₁R₂,        (C₁-C₆)alkyl-COOH, (C₂-C₆)alkenyl-COOH, phenyl and        (C₁-C₃)alkylphenyl,

in which, in turn,

R₁ and R₂, which may be identical or different, are (C₁-C₃)alkyl; andthe physiologically acceptable addition salts, stereoisomers,enantiomers, hydrates, solvates and polymorphic forms thereof.

The chain of the various alkyl groups that may be present in thecompound of formula (I) may be linear or branched.

In the case of certain substituents, the compound of formula (I)according to the present invention may contain an asymmetric carbon atomand may thus be in the form of stereoisomers and enantiomers. Typicalexamples of such substituents are 2-butanol, 2-methylbutyl, 2-butenoicacid, 2-methylpropanoic acid and 1,2-pentane diol.

Preferably, the halogen is bromine, chlorine or fluorine.

Preferred meanings of X are halogen, (C₁-C₃)alkyl, trifluoromethyl,nitro, cyano and (C₁-C₃)alkoxy. Particularly preferred meanings of X areCl, Br, F, trifluoromethyl and nitro.

Preferred meanings of Y and Z are H, halogen, nitro, COOH, (C₁-C₃)alkyl,trifluoromethyl and (C₁-C₃)alkoxy. Particularly preferred meanings of Yand Z are Cl, Br, F, trifluoromethyl, nitro, COOH, methyl, ethyl,methoxy and ethoxy.

Preferred meanings of R are methyl, ethyl, propyl, isopropyl andcyclohexyl.

Preferred meanings of R′ are H, methyl, ethyl, propyl, isopropyl andcyclohexyl.

Preferred meanings of A are phenyl, naphthyl and pyridine optionallysubstituted with 1 or 2 substituents, which may be identical ordifferent, selected from halogen, (C₁-C₃)alkyl, (C₁-C₃)alkoxy andbenzyloxy.

A first particularly preferred meaning of A is phenyl optionallysubstituted with 1 or 2 substituents, which may be identical ordifferent, selected from Br, Cl, F, methyl, ethyl, methoxy, ethoxy andbenzyloxy.

A second particularly preferred meaning of A is naphthyl optionallysubstituted with 1 or 2 substituents, which may be identical ordifferent, selected from Br, Cl, F, methyl, ethyl, methoxy, ethoxy andbenzyloxy.

A third particularly preferred meaning of A is pyridine optionallysubstituted with 1 or 2 substituents, which may be identical ordifferent, selected from Br, Cl, F, methyl, ethyl, methoxy, ethoxy andbenzyloxy.

Depending on the nature of the substituents, the compound of formula (I)may form addition salts with physiologically acceptable organic ormineral acids or bases.

Typical examples of physiologically acceptable mineral acids arehydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid andnitric acid.

Typical examples of suitable physiologically acceptable organic acidsare acetic acid, ascorbic acid, benzoic acid, citric acid, fumaric acid,lactic acid, maleic acid, methanesulfonic acid, oxalic acid,para-toluenesulfonic acid, succinic acid, tannic acid and tartaric acid.

Typical examples of suitable physiologically acceptable mineral basesare: ammonia, calcium, magnesium, sodium and potassium.

Typical examples of suitable physiologically acceptable organic basesare: arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine,diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol,ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine,N-methylglucamine, glucamine, glucosamine, histidine,N-(2-hydroxyethyl)piperidine, N-(2-hydroxyethyl)pyrrolidine,isopropylamine, lysine, methylglucamine, morpholine, piperazine,piperidine, theobromine, triethylamine, trimethylamine, tripropylamineand tromethamine.

In a second aspect, the present invention relates to a process forpreparing a 2-arylindole compound substituted in position 5, of formula(I):

-   -   in which A, X, Y, Z, W, R and R′ have the meanings given above,        and the physiologically acceptable addition salts,        stereoisomers, enantiomers, hydrates, sulfates and polymorphic        forms thereof,    -   a) by reacting a compound of formula (II):

-   -   -   in which        -   X, Y and Z have the meanings given above, and        -   Q is a halogen atom or a hydroxy group,        -   with a compound of formula (III):

-   -   -   in which        -   R and R′ have the meanings given above, and        -   G has the same meanings as A or is a hydrogen atom,        -   to give a compound of formula (IV):

-   -   -   in which        -   X, Y, Z, W, G, R and R′ have the meanings given above, and

    -   b) when G is H, by reacting the compound of formula (IV) with a        compound of formula (V):

IA  (V)

-   -   -   in which        -   I is an iodine atom, and        -   A has the meanings given above, to give the compound of            formula (I), and

    -   c) forming, if so desired, a physiologically acceptable addition        salt of the compound of formula (IV) from step (a) in which G is        other than H or of the compound of formula (I) from step (b).

Clearly, the compound of formula (IV) in which G is other than H is noneother than the compound of formula (I). Thus, in the abovementioned step(c), a physiologically acceptable addition salt of the compound offormula (I) of the present invention is always obtained.

According to a first embodiment, the abovementioned step (a) isperformed by reacting a compound of formula (II) in which Q is Cl withan amine of formula (III) in the presence of a suitable acid acceptoraccording to standard techniques.

According to a second embodiment, the abovementioned step (a) isperformed by reacting a compound of formula (II) in which Q is OH withan amine of formula (III) in the presence of a suitable coupling agentaccording to standard techniques.

The reaction in the abovementioned step (b) between a compound offormula (IV) in which G is H and an aryl iodide of formula (V) is alsoperformed according to standard techniques.

The intermediate compounds of formula (III) are novel.

According to a third aspect, the present invention also relates to acompound of formula (III):

-   -   in which    -   R is a (C₁-C₆)alkyl or (C₃-C₇)cycloalkyl group optionally        substituted with 1 to 3 hydroxy groups;    -   R′ is an H atom or a (C₁-C₆)alkyl or (C₃-C₇)cycloalkyl group        optionally substituted with 1 to 3 hydroxy groups,    -   G is a phenyl, naphthyl or pyridine group optionally substituted        with 1 to 3 substituents, which may be identical or different,        selected from halogen, (C₁-C₆)alkyl optionally substituted with        1 to 3 hydroxy groups, trifluoromethyl, nitro, amino,        di(C₁-C₃)alkylamino, hydroxy, (C₁-C₃)alkoxy, benzyloxy, COOH,        COOR, SO₂CH₃, SO₂NHCH₃, NHSO₂CH₃, POR₁R₂, OPOR₁R₂,        (C₁-C₆)alkyl-COOH, (C₂-C₆)alkenyl-COOH, phenyl and        (C₁-C₃)alkylphenyl,    -   in which, in turn,

R₁ and R₂, which may be identical or different, are (C₁-C₃)alkyl; oncondition, however, that G is not an unsubstituted phenyl group when Ris methyl and R′ is H.

Preferred meanings of R are methyl, ethyl, propyl, isopropyl andcyclohexyl.

Preferred meanings of R′ are H, methyl, ethyl, propyl, isopropyl andcyclohexyl.

A first particularly preferred meaning of A is phenyl substituted with 1or 2 substituents, which may be identical or different, selected fromBr, Cl, F, methyl, ethyl, methoxy, ethoxy and benzyloxy.

A second particularly preferred meaning of A is naphthyl optionallysubstituted with 1 or 2 substituents, which may be identical ordifferent, selected from Br, Cl, F, methyl, ethyl, methoxy, ethoxy andbenzyloxy.

A third particularly preferred meaning of A is pyridine optionallysubstituted with 1 or 2 substituents, which may be identical ordifferent, selected from Br, Cl, F, methyl, ethyl, methoxy, ethoxy andbenzyloxy.

The investigations on the biological properties of the compound offormula (I) according to the present invention demonstrated that it hasan unexpected selective property of inhibiting mPGES-1 and pronouncedanti-nociceptive activity in inflammatory pain.

In a fourth aspect, the present invention thus relates to apharmaceutical composition containing an effective amount of a compoundof formula (I), or of a physiologically acceptable addition salt,stereoisomer, enantiomer, hydrate, solvate or polymorphic form thereof,and at least one pharmaceutically acceptable inert ingredient.

In the present description and in the claims, the term “effectiveamount” refers to an amount that gives an evaluable improvement in atleast one symptom or parameter of a specific disorder.

The pharmaceutical composition according to the present invention willbe used in the treatment or prevention of disorders associated with theproduction of prostaglandin E₂ (PGE₂), for instance inflammatoryprocesses, pain, tumours, neurodegenerative disorders andatherosclerosis.

Advantageously, the pharmaceutical composition according to the presentinvention will be used in the treatment of pain in chronic inflammatorypathologies such as arthritis, or of tumours, particularly colorectal,oesophageal, breast, lung and bladder tumours.

Preferably, the pharmaceutical compositions of the present invention areprepared in suitable dosage forms comprising an effective dose of atleast one compound of formula (I) or of a physiologically acceptableaddition salt, stereoisomer, enantiomer, hydrate, solvate or polymorphicform thereof, and at least one pharmaceutically acceptable inertingredient.

Examples of suitable dosage forms are tablets, capsules, coated tablets,granules, solutions and syrups for oral administration; creams,ointments and antiseptic plasters for topical administration;suppositories for rectal administration and sterile solutions foradministration by injection or aerosol or ophthalmic administration.

The dosage forms may also contain other conventional ingredients, forinstance: preserving agents, stabilizers, surfactants, buffers, saltsfor regulating the osmotic pressure, emulsifiers, sweeteners, colorants,flavourings and the like.

If required for particular therapies, the pharmaceutical composition ofthe present invention may contain other pharmacologically activeingredients whose simultaneous administration is beneficial.

The amount of compound of formula (I) or of a physiologically acceptableaddition salt, stereoisomer, enantiomer, hydrate, solvate or polymorphicform thereof, and at least one pharmaceutically acceptable inertingredient in the pharmaceutical composition of the present inventionmay vary within a wide range depending on known factors, for instancethe type of disease to be treated, the severity of the disease, the bodyweight of the patient, the dosage form, the chosen route ofadministration, the number of daily administrations and the efficacy ofthe chosen compound of formula (I). However, the optimum amount may beeasily and routinely determined by a person skilled in the art.

Typically, the amount of compound of formula (I) or of a physiologicallyacceptable addition salt, stereoisomer, enantiomer, hydrate, solvate orpolymorphic form thereof, and at least one pharmaceutically acceptableinert ingredient in the pharmaceutical composition of the presentinvention will be such that it provides a level of administration ofbetween 0.0001 and 100 mg/kg/day and even more preferably between 0.01and 10 mg/kg/day.

Clearly, the pharmaceutical formations of the present invention do notnecessarily need to contain the entire amount of the compound of formula(I) since the said effective amount may be added by means ofadministration of a plurality of doses of the pharmaceutical compositionof the present invention.

The dosage forms of the pharmaceutical composition of the presentinvention may be prepared according to techniques that are well known topharmaceutical chemists, including mixing, granulation, compression,dissolution, sterilization and the like.

The examples that follow serve to further illustrate the inventionwithout, however, limiting it.

EXAMPLE 1 Preparation of Intermediate Compounds a)1-methyl-2-phenyl-1H-indol-5-amine

To a solution of 2-phenyl-5-nitroindole (prepared as described in J.Org. Chem. (1966), 31(1), 65-9) (1 g; 4.2 mmol) in DMF (10 ml) was addedsodium hydride (50% suspension) (0.20 g; 4.2 mmol); the mixture was leftunder stirring for 30 minutes.

To the mixture thus obtained was then added dropwise iodomethane (0.60g; 4.2 mmol) dissolved in DMF (10 ml) and the resulting mixture was leftunder stirring at room temperature for 18 hours. The mixture was thenpoured into water (50 ml) and extracted with ethyl acetate (2×50 ml).

The organic phases were combined and dried over Na₂SO₄, and the solutionwas evaporated under reduced pressure. The residue thus obtained waspurified by flash chromatography (eluent: 7/3 hexane/ethyl acetate) togive 1 g of 1-methyl-5-nitro-2-phenyl-1H-indole, which was used in thefollowing reaction without any further purification.

¹H NMR (300 MHz, DMSO-d₆) δ ppm 3.83 (s, 3H) 6.88 (d, J=0.70 Hz, 1H)7.47-7.68 (m, 5H) 7.73 (d, J=9.06 Hz, 1H) 8.08 (dd, J=9.06, 2.34 Hz, 1H)8.59 (d, J=2.05 Hz, 1H)

To a suspension of 1-methyl-5-nitro-2-phenyl-1H-indole (1 g; 4 mmol) in95° ethanol (100 ml) was added 10% Pd/C (0.1 g; 0.1 mmol) and themixture underwent hydrogenation in a Parr hydrogenator (30 psi) for 4hours.

The reaction mixture was filtered and the solution was evaporated underreduced pressure to give 1-methyl-2-phenyl-1H-indol-5-amine (0.8 g),which was used without any further purification.

¹H NMR (300 MHz, DMSO-d₆) δ ppm 3.64 (s, 3H) 4.51 (br, s, 2H) 6.28 (d,J=0.88 Hz, 1H) 6.59 (dd, J=8.62, 2.19 Hz, 1H) 6.70 (d, J=1.46 Hz, 1H)7.17 (d, J=8.48 Hz, 1H) 7.25-7.59 (m, 5H)

b) 1-ethyl-2-phenyl-1H-indol-5-amine

The process described above in Example 1a) was used, except thatiodoethane was used instead of iodomethane.

1-ethyl-5-nitro-2-phenyl-1H-indole: ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.21(t, J=7.16 Hz, 3H) 4.30 (q, J=7.16 Hz, 2H) 6.83 (d, J=0.58 Hz, 1H)7.48-7.63 (m, 5H) 7.77 (d, J=9.21 Hz, 1H) 8.07 (dd, J=9.21, 2.34 Hz, 1H)8.58 (d, J=2.34 Hz, 1H)

1-ethyl-2-phenyl-1H-indol-5-amine: ¹H NMR (300 MHZ, chloroform-d) δ ppm1.28 (t, J=6.94 Hz, 3H) 3.59 (br, s, 2H) 4.13 (q, J=7.16 Hz, 2H) 6.37(d, J=0.73 Hz, 1H) 6.82 (dd, J=8.48, 2.19 Hz, 1H) 7.09 (d, J=1.90 Hz,1H) 7.23 (d, J=8.62 Hz, 1H) 7.33-7.54 (m, 5H)

c) 1-isopropyl-2-phenyl-1H-indol-5-amine

The process described above in step a) was used, except that isopropylbromide was used instead of iodomethane.

1-isopropyl-5-nitro-2-phenyl-1H-indole:

Monoisotopic mass=280.1; LC/MS (M+H)⁺=281.2

d) 1-ethyl-2-(2-fluorophenyl)-1H-indol-5-amine

To a suspension containing caesium acetate dried under vacuum overnightat 140° C. (3.6 g; 19 mmol) in N,N-dimethylacetamide (DMA, 5 ml), underan inert atmosphere, were added palladium acetate (12 mg; 0.05 mmol),triphenylphosphine (55 mg; 0.21 mmol), 1-ethyl-5-nitro-1H-indole (2 g;10 mmol) (prepared as described in Bioorg. Med. Chem. 13 (2005),3531-3541) and 1-iodo-2-fluorobenzene (2.53 g; 11 mmol).

The reaction mixture was left under stirring at 140° C. under an inertatmosphere for 18 hours. The mixture was then cooled to roomtemperature, dichloromethane (50 ml) was added and the mixture thusobtained was filtered under vacuum through Celite.

The organic solution was transferred into a separating funnel, washedwith H₂O (2×50 ml) and dried over Na₂SO₄.

The organic solvent was removed by evaporation under reduced pressureand the residue was purified by flash chromatography on silica gel togive 1-ethyl-2-(2-fluorophenyl)-5-nitro-1H-indole (0.7 g), which wasused without any further purification.

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.15 (t, J=7.16 Hz, 3H) 4.18 (q, J=7.02Hz, 2H) 6.87 (s, 1H) 7.35-7.50 (m, 2H) 7.51-7.70 (m, 2H) 7.79 (d, J=9.06Hz, 1H) 8.10 (dd, J=9.06, 2.34 Hz, 1H) 8.62 (d, J=2.34 Hz, 1H)

To a suspension containing 1-ethyl-2-(2-fluorophenyl)-5-nitro-1H-indole(0.78 g; 2.75 mmol) in 95° ethanol (100 ml) was added 10% Pd/C (0.1 g;0.1 mmol) and the mixture underwent hydrogenation in a Parr hydrogenator(30 psi) for 4 hours. The mixture was filtered and the solution wasevaporated under reduced pressure to give1-ethyl-2-(2-fluorophenyl)-1H-indol-5-amine (0.8 g), which was usedwithout any further purification.

e) 1-ethyl-2-(3-fluorophenyl)-1H-indol-5-amine

The process described above in Example 1d) was used, except that3-fluoro-1-iodobenzene was used instead of 1-iodo-2-fluorobenzene.

1-ethyl-2-(3-fluorophenyl)-5-nitro-1H-indole: ¹H NMR (300 MHz, DMSO-d₆)δ ppm 1.20 (t, J=7.16 Hz, 3H) 4.32 (q, J=7.31 Hz, 2H) 6.90 (s, 1H)7.31-7.51 (m, 3H) 7.55-7.67 (m, 1H) 7.79 (d, J=9.06 Hz, 1H) 8.09 (dd,J=9.06, 2.34 Hz, 1H) 8.59 (d, J=2.05 Hz, 1H)

f) 1-ethyl-2-(4-fluorophenyl)-1H-indol-5-amine

The process described above in Example 1d) was used, except that4-fluoro-1-iodobenzene was used instead of 1-iodo-2-fluorobenzene.

1-ethyl-2-(4-fluorophenyl)-5-nitro-1H-indole: ¹H NMR (300 MHz, DMSO-d₆)δ ppm 1.19 (t, J=7.16 Hz, 3H) 4.28 (q, J=7.02 Hz, 2H) 6.83 (s, 1H)7.34-7.45 (m, 2H) 7.60-7.68 (m, 2H) 7.77 (d, J=9.35 Hz, 1H) 8.07 (dd,J=9.35, 2.34 Hz, 1H) 8.58 (d, J=2.34 Hz, 1H)

1-ethyl-2-(4-fluorophenyl)-1H-indol-5-amine: ¹H NMR (300 MHz,chloroform-d) δ ppm 1.24 (t, J=7.16 Hz, 3H) 4.08 (q, J=7.16 Hz, 2H) 6.33(s, 1H) 6.94 (dd, J=8.55, 2.27 Hz, 1H) 7.09-7.25 (m, 4H) 7.41 (d,J=8.77, 5.41 Hz, 2H)

g) 1-ethyl-3-methyl-2-phenyl-1H-indol-5-amine

The process described above in Example 1a) was used, except that2-phenyl-3-methyl-5-nitroindole (prepared as described in Tetrahedron1965, Vol. 21, 823-829) and iodoethane were used instead of2-phenyl-5-nitroindole and iodomethane.

1-ethyl-3-methyl-5-nitro-2-phenyl-1H-indole: ¹H NMR (300 MHz, DMSO-d₆) δppm 1.10 (t, J=7.10 Hz, 3H) 2.23 (s, 3H), 4.16 (q, J=7.27 Hz, 2H)7.44-7.63 (m, 5H) 7.71 (d, J=9.25 Hz, 1H) 8.07 (dd, J=9.25, 2.31 Hz, 1H)8.53 (d, J=2.31 Hz, 1H)

1-ethyl-3-methyl-2-phenyl-1H-indol-5-amine: ¹H NMR (300 MHz,chloroform-d) δ ppm 1.17 (t, J=7.16 Hz, 3H) 2.16 (s, 3H) 3.35 (br, s,2H) 4.00 (q, J=7.16 Hz, 2H) 6.76 (dd, J=8.48, 2.19 Hz, 1H) 6.96 (d,J=1.75 Hz, 1H) 7.17 (d, J=8.33 Hz, 1H) 7.31-7.53 (m, 5H)

h) 5-amino-2-phenyl-1-cyclohexylindole

To a suspension of caesium acetate dried under vacuum overnight at 140°C. (1.8 g; 9.5 mmol) in N,N-dimethylacetamide (5 ml), under an inertatmosphere, were added palladium acetate (6 mg; 0.05 mmol),triphenylphosphine (28 mg; 0.1 mmol), 1-cyclohexylindole (prepared asdescribed in Synthesis 1977, 5, 335-336) (1 g; 5 mmol) and1-iodo-4-methylbenzene (1.26 g; 6 mmol).

The reaction mixture was left under stirring at 140° C. under an inertatmosphere for 18 hours. It was then cooled to room temperature anddichloromethane (50 ml) was added. The reaction mixture was filteredunder vacuum through Celite. The filtrate was transferred into aseparating funnel and the organic phase was washed with H₂O (2×50 ml)and dried over Na₂SO₄.

The organic solvent was removed by evaporation under reduced pressureand the residue was purified by flash chromatography on silica gel (97/3hexane/ethyl acetate) to give 1-cyclohexyl-2-(4-methylphenyl)-1H-indole(200 mg), which was used without any further purification.

¹H NMR (300 MHz, chloroform-d₆) δ ppm 1.13-1.98 (m, 8H) 2.25-2.41 (m,2H) 2.43 (s, 3H) 4.21 (tt, J=12.42, 3.80 Hz, 1H) 6.42 (br. s., 1H)7.05-7.11 (m, 1H) 7.15 (ddd, J=7.90, 7.20, 1.30 Hz, 1H) 7.22-7.35 (m,4H) 7.57-7.67 (m, 2H)

To a solution of 1-cyclohexyl-2-(4-methylphenyl)-1H-indole (100 mg, 0.3mmol) in 2 ml of concentrated H₂SO₄ at 5° C. was added dropwise asolution of NaNO₃ (34 mg; 0.4 mmol) in H₂SO₄ (1 ml).

Once the addition was complete, the mixture was left under stirring at5° C. for 10 minutes. It was then poured into H₂O and ice (10 ml) andthe solid thus formed was filtered off and purified by flashchromatography on silica gel (99/1 hexane/ethyl acetate) to give1-cyclohexyl-2-(4-methylphenyl)-5-nitro-1H-indole (45 mg), which wasused without any further purification.

¹H NMR (300 MHz, chloroform-d) δ ppm 1.15-1.42 (m, 4H) 1.64-2.01 (m, 4H)2.16-2.41 (m, 2H) 2.45 (s, 3H) 4.24 (tt, J=12.42, 3.80 Hz, 1H) 6.59 (s,1H) 7.28-7.35 (m, 4H) 7.64 (d, J=9.35 Hz, 1H) 8.06 (dd, J=9.35, 2.34 Hz,1H) 8.54 (d, J=2.34 Hz, 1H)

To a suspension of 1-cyclohexyl-2-(4-methylphenyl)-5-nitro-1H-indole (45mg; 0.13 mmol) in absolute ethanol (5 ml) was added stannous chloridedihydrate (152 mg; 0.67 mmol) and the mixture was left under stirring at70° C. for 18 hours. The reaction mixture was cooled to room temperatureand then poured into H₂O and ice (20 ml), NaHCO₃ (saturated solution)was added to pH 8 and the mixture was left under stirring for 20minutes.

The mixture was then poured into a separating funnel and extracted withethyl acetate (2×30 ml). The organic phases were combined and dried overNa₂SO₄, and the solvent was removed by evaporation under reducedpressure to give 5-amino-2-(4-methylphenyl)-1-cyclohexylindole (30 mg),which was used without any further purification.

¹H NMR (300 MHz, chloroform-d₆) δ ppm 1.12-1.42 (m, 4H) 1.62-1.94 (m,4H), 2.17-2.38 (m, 2H) 2.41 (s, 3H) 4.05-4.20 (m, 1H) 4.23 (br. s., 2H)6.25 (s, 1H) 6.69 (dd, J=8.62, 2.19 Hz, 1H) 6.98 (d, J=2.34 Hz, 1H)7.19-7.33 (m, 4H) 7.45 (d, J=8.77 Hz, 1H)

i) 2-chloro-N-(1-ethyl-1H-indol-5-yl)benzamide

To a solution of 1-ethyl-1H-indol-5-amine (prepared as described inBioorg. Med. Chem. 13 (2005), 3531-3541) (27 g; 170 mmol) indichloromethane (300 ml) was added N,N-diisopropylethylenediamine (26.1g; 202 mmol), followed by dropwise addition of 2-chlorobenzoyl chloride(35.4 g; 202 mmol) dissolved in dichloromethane (50 ml).

Once the additions were complete, the mixture was left under stirring atroom temperature for 2 hours. Water (400 ml) was then added and theorganic phase was separated out and dried over Na₂SO₄.

The organic solution was evaporated under reduced pressure. The crudeproduct obtained was purified by crystallization with ethyl acetate togive the desired product (37 g).

¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.35 (t, J=7.27 Hz, 3H) 4.19 (q, J=7.05Hz, 2H) 6.41 (dd, J=2.97, 0.66 Hz, 1H) 7.34-7.60 (m, 7H) 8.00 (d, J=1.32Hz, 1H) 10.26 (s, 1H)

EXAMPLE 2 Preparation of Compounds of the Invention a) Example of aFirst Variant of the Preparation Process:

To a solution of a 5-aminoindole (III) (2 mmol) in dichloromethane (10ml) was added triethylamine (2.2 mmol), followed by dropwise addition ofan acyl chloride (II) (2.2 mmol) dissolved in dichloromethane (10 ml).Once the additions were complete, the mixture was left under stirring atroom temperature for 20 hours. Water (50 ml) was then added and theorganic phase was separated out and dried over Na₂SO₄. The solution wasevaporated under reduced pressure. The crude product obtained waspurified to give compound (I) in which X, Y, Z, R, R′ and A have themeanings given above.

b) Example of a Second Variant of the Preparation Process:

To a suspension of a 5-aminoindole (III) (0.9 mmol) were added AmberlystA21 resin (0.9 g) in dichloromethane (3 ml) and an acyl chloride (II)(0.28 mmol) in dichloromethane (3 ml). The mixture was left understirring for 20 hours. The Amberlyst A21 resin was then removed byfiltration and washed with dichloromethane (5 ml). The organic phaseswere combined, diluted with dimethylformamide (1 ml) and stirred withAmberlyst 15 resin (0.9 g) for 5 hours. This treatment was repeatedtwice. The Amberlyst 15 resin was removed by filtration and the solutionwas evaporated under centrifuge to give compound (I) in which X, Y, Z,R, R′ and A have the meanings indicated above.

c) Example of a Third Variant of the Preparation Process:

Under an inert atmosphere, a benzoic acid (II) (0.67 mmol) and a5-aminoindole (III) (0.45 mmol) were dissolved in dichloromethane (8 ml)and dimethylformamide (0.8 ml). After leaving the mixture stirring atroom temperature for 10 minutes, PS-carbodiimide resin (0.73 g) wasadded.

After leaving the reaction mixture stirring for 20 hours, the resin wasremoved by filtration and washed with dichloromethane (2×5 ml). Thesolution was evaporated under centrifugation to give compound (I) inwhich X, Y, Z, R, R′ and A have the meanings given above.

d) Example of a Fourth Variant of the Preparation Process:

To a solution of a benzoic acid (II) (10 mmol) in dimethylformamide (40ml) with stirring at 0° C. were added 1-hydroxybenzotriazol (HOBt) (10mmol) and dicyclohexylcarbodiimide (DCC) (10 mmol). The mixture was leftunder stirring at 0° C. for 30 minutes and a 5-aminoindole (III) (9mmol) dissolved in dimethylformamide (20 ml) was added.

The mixture was left under stirring at 0° C. for a further 30 minutes,and then at room temperature for 18 hours. The mixture was filtered, 2Nhydrochloric acid was added to pH 2, and the precipitate thus formed wasfiltered off and purified to give compound (I) in which X, Y, Z, R, R′and A have the meanings given above.

e) Example of a Fifth Variant of the Preparation Process:

To a suspension of caesium acetate dried under vacuum overnight at 140°C. (6.02 mmol) in N,N-dimethylacetamide (DMA) (3 ml), under an inertatmosphere, were added palladium acetate (0.017 mmol),triphenylphosphine (0.067 mmol), indole (V) (3.35 mmol) and an aryliodide (V) (3.68 mmol).

The reaction mixture was left under stirring at 140° C. under an inertatmosphere for 18 hours. The reaction mixture was cooled to roomtemperature, dichloromethane (50 ml) was added and the resulting mixturewas filtered under vacuum through Celite. The filtered organic solutionwas transferred into a separating funnel. The organic phase was washedwith H₂O (2×50 ml), dried over Na₂SO₄ and evaporated under reducedpressure.

The residue was purified to give compound (I) in which X, Y, Z, R, R′and A have the meanings given above.

The compounds of formula (I) shown in Table 1 below, in which

Purification A=Crystallization

Purification B=Flash chromatography on silica gel

i-PrOH=Isopropanol

(i-Pr)₂O=Diisopropyl ether

EtOAc=Ethyl acetate

Hex=Hexane

EtOH=Ethanol

CHCl₃=Chloroform

MeOH=Methanol

AcOH=Acetic acid

were thus prepared.

TABLE 1 Ex- Mono- Com- am- isotopic LC/MS pound Structural Formula plePurification Mass (M + H)⁺ ¹H NMR (300 MHz)  1

2(a) A (EtOH 95°) 360.1 361.4 DMSO-d₆ δ ppm 3.75 (s, 3 H) 6.58 (s, 1 H)7.36-7.70 (m, 11 H) 8.06 (s, 1 H) 10.33 (s, 1 H)  2

2(a) A (i-prOH/ (i-pr)₂O =1/1) 374.1 375.4 DMSO-d₆ δ ppm 1.19 (dd, J =7.00 Hz, 3 H) 4.21 (q, J = 7.10 Hz, 2 H) 6.53 (s, 1 H) 7.39-7.63 (m, 11H) 8.04 (d, J = 1.65 Hz, 1 H) 10.31 (s, 1 H)  3

2(a) A (EtOH 95°) 388.1 389.3 DMSO-d₆ δ ppm 1.54 (d, J = 6.95 Hz, 6 H)4.51-4.68 (m, J = 7.00, 7.00, 7.00, 7.00, 7.00, 7.00 Hz, 1 H) 6.43 (s, 1H) 7.32-7.72 (m, 11 H) 8.04 (d, J = 1.83 Hz, 1 H) 10.31 (s, 1 H)  4

2(a) B (Es/AcOEt = 8/2) DMSO-d₆ δ ppm 1.13 (t, J = 6.94 Hz, 3 H) 4.08(q, J = 6.72 Hz, 2 H) 6.54 (s, 1 H) 7.30-7.67 (m, 10 H) 8.07 (d, J =1.65 Hz, 1 H) 10.34 (s, 1 H)  5

2(a) B (Es/AcOEt = 8/2) DMSO-d₆ δ ppm 1.19 (t, J = 7.10 Hz, 3 H) 4.23(q, J = 7.27 Hz, 2 H) 6.61 (s, 1 H) 7.23-7.65 (m, 10 H) 8.06 (d, J =1.98 Hz, 1 H) 10.34 (s, 1 H)  6

2(a) B (Es/AcOEt = 7/3) DMSO-d₆ δ ppm 1.18 (t, J = 7.00 Hz, 3 H) 4.19(q, J = 7.27 Hz (2 H) 6.53 (s, 1 H) 7.29-7.67 (m, 10 H) 8.05 (d, J =1.65 Hz, 1 H) 10.32 (s, 1 H)  7

2(a) B (Es/AcOEt = 9/1) DMSO-d₆ δ ppm 1.08 (t, J = 7.14 Hz, 3 H) 2.16(s, 3 H) 4.07 (q, J = 7.03 Hz, 2 H) 7.37- 7.64 (m, 11 H) 8.02 (d, J =1.39 Hz, 1 H) 10.32 (s, 1 H)  8

2(a) B (Es/AcOEt = 9/1) 442.2 443.3 CHLOROFORM-d δ ppm 1.11- 1.44 (m, 4H) 1.64-1.97 (m, 4 H) 2.23-2.41 (m, 2 H) 2.43 (s, 3 H) 4.20 (tt, J =12.35, 3.65, 3.51 Hz, 1 H) 6.42 (s, 1 H) 7.21-7.50 (m, 8 H) 7.61 (d, J =8.77 Hz, 1 H) 7.77-7.84 (m, 1 H) 7.87 (s, 1 H) 7.93 (d, J = 2.05 Hz, 1H)  9

2(b) — 408.1 409.4 10

2(b) — 408.1 409.4 11

2(b) — 370.2 371.3 12

2(c) — 419.1 420.3 13

2(c) — 408.1 409.4 14

2(c) — 418.1 419.3 15

2(c) — 354.2 355.4 16

2(c) — 385.1 386.3 17

2(d) B CHCl₃/MeOH/ AcOH = 95/5/0.1 462.1 463.3 DMSO-d₆ δ ppm 1.20 (t, J= 7.06 Hz, 3 H) 4.21 (q, J = 6.86 Hz, 2 H) 6.54 (s, 1 H) 7.37-7.61 (m, 7H) 7.70 (d, J = 7.67 Hz, 1 H) 7.98-8.07 (m, 2 H) 8.17 (d, J = 1.21 Hz, 1H) 10.42 (s, 1 H) 13.46 (br, s,, 1 H) 18

2(e) B (Es/AcOEt = 8/2) 388.1 389.3 DMSO-d₆ δ ppm 1.05 (t, J = 7.05 Hz,3 H) 2.16 (s, 3 H) 3.95 (q, J = 6.97 Hz, 2 H) 6.39 (s, 1 H) 7.26-7.65(m, 10 H) 8.02 (d, J = 1.57 Hz, 1 H) 10.31 (s, 1 H) 19

2(e) B (Es/AcOEt = 8/2) 388.1 389.4 DMSO-d₆ δ ppm 1.19 (dd, J = 7.00 Hz,3 H) 2.40 (s, 3 H) 4.21 (q, J = 6.94 Hz, 2 H) 6.50 (s, 1 H) 7.20-7.67(m, 10 H) 8.03 (d, J = 1.65 Hz, 1 H) 10.32 (s, 1 H) 20

2(e) B (Es/AcOEt = 8/2) 388.1 389.2 DMSO-d₆ δ ppm 1.18 (t, J = 6.94 Hz,3 H) 2.39 (s, 3 H) 4.19 (q, J = 6.94 Hz, 2 H) 6.48 (s, 1 H) 7.28-7.63(m, 10 H) 8.02 (d, J = 1.65 Hz, 1 H) 10.31 (s, 1 H) 21

2(e) B (Es/AcOEt = 8/2) 418.1 419.4 DMSO-d₆ δ ppm 1.19 (t, J = 7.10 Hz,3 H) 1.37 (t, J = 6.94 Hz, 3 H) 4.10 (q, J = 6.94 Hz, 2 H) 4.13-4.23 (m,2 H) 6.44 (s, 1 H) 7.02-7.11 (m, 2 H) 7.24-7.77 (m, 8 H) 8.01 (d, J =1.65 Hz, 1 H) 10.30 (s, 1 H) 22

2(e) B (Es/AcOEt = 7/3) 480.2 481.4 DMSO-d₆ δ ppm 1.19 (t, J = 7.02 Hz,3 H) 4.15-4.22 (m, 2 H) 5.19 (s, 2 H) 6.45 (s, 1 H) 7.12-7.23 (m, 2 H)7.25-7.64 (m, 13 H) 8.00-8.03 (m, 1 H) 10.30 (s, 1 H) 23

2(e) B (Es/AcOEt = 85/15) 430.2 431.5 DMSO-d₆ δ ppm 1.22 (t, J = 7.10Hz, 3 H) 1.35 (s, 9 H) 4.20 (q, J = 7.10 Hz, 2 H) 6.49 (s, 1 H)7.37-7.64 (m, 10 H) 8.03 (d, J = 1.65 Hz, 1 H) 10.31 (s, 1 H) 24

2(e) B (Es/AcOEt = 8/2) 424.1 425.3 DMSO-d₆ δ ppm 1.00 (t, J = 7.10 Hz,3 H) 3.62-4.21 (m, 2 H) 6.57 (d, J = 0.66 Hz, 1 H) 7.41-7.71 (m, 11 H)8.01-8.12 (m, 3 H) 10.35 (s, 1 H) 25

2(e) B (Es/AcOEt = 85/15) 422.1 423.2 DMSO-d₆ δ ppm 1.14-1.22 (m, J =6.94, 6.94 Hz, 3 H) 2.43 (s, 3 H) 4.21 (q, J = 6.94 Hz, 2 H) 6.55 (s, 1H) 7.36-7.62 (m, 9 H) 8.04 (d, J = 1.65 Hz, 1 H) 10.33 (s, 1 H) 26

2(e) B (Es/AcOEt = 8/2) 442.1 443.3 DMSO-d₆ δ ppm 1.20 (t, J = 7.10 Hz,3 H) 4.25 (q, J = 7.10 Hz, 2 H) 6.68 (s, 1 H) 7.41- 7.64 (m, 6 H)7.76-7.92 (m, 4 H) 8.09 (d, J = 1.65 Hz, 1 H) 10.36 (s, 1 H) 27

2(e) B (Es/AcOEt = 7/3) 375.1 376.3 DMSO-d₆ δ ppm 1.20 (t, J = 7.10 Hz,3 H) 4.22 (q, J = 7.05 Hz, 2 H) 6.66 (s, 1 H) 7.41- 7.64 (m, 7 H) 8.00(dt, J = 8.09, 1.98, 1.82 Hz, 1 H) 8.08 (t, J = 1.88 Hz, 1 H) 8.65 (dd,J = 4.62, 1.65 Hz, 1 H) 8.78 (dd, J = 2.31, 0.99 Hz, 1 H) 10.35 (s, 1 H)28

2(e) B (Es/AcOEt = 8/2) 422.1 423.0 DMSO-d₆ δ ppm 1.06 (t, J = 7.10 Hz,3 H) 2.18 (s, 3 H) 3.94 (br, s,, 2 H) 6.43 (s, 1 H) 7.30-7.63 (m, 9 H)8.04 (d, J = 1.65 Hz, 1 H) 10.32 (s, 1 H) 29

2(e) B (Es/AcOEt = 8/2) 402.1 403.3 DMSO-d₆ δ ppm 1.18 (t, J = 7.10 Hz,3 H) 2.29 (s, 3 H) 2.31 (s, 3 H) 4.19 (q, J = 6.94 Hz, 2 H) 6.46 (s, 1H) 7.21-7.63 (m, 9 H) 8.02 (d, J = 1.98 Hz, 1 H) 10.30 (s, 1 H) 30

2(e) B (Es/AcOEt = 8/2) 404.1 405.4 DMSO-d₆ δ ppm 1.19 (t, J = 7.10 Hz,3 H) 3.83 (s, 3 H) 4.18 (q, J = 6.94 Hz, 2 H) 6.45 (s, 1 H) 7.04-7.13(m, 2 H) 7.36- 7.63 (m, 8 H) 8.01 (d, J = 1.65 Hz, 1 H) 10.30 (s, 1 H)

EXAMPLE 3 In Vitro Biological Activity

The test used makes it possible to evaluate the inhibitory capacity ofthe test compounds on the production of PGE₂ and the selectivityrelative to the production of PGF_(2α). The human pulmonaryadenocarcinoma cell line A549 was used, which is particularly sensitiveto stimulation with proinflammatory cytokines, for instance IL-1_(β),and, in response to this stimulation, is particularly active in theproduction and release of two prostanoids: PGE₂ and PGF_(2α) (Thoren S.Jakobsson P-J, 2000).

The cells were stimulated with IL-1_(β) (10 ng/ml) and simultaneouslytreated with the test compound for 22 hours in a suitable culture medium(DMEM—Dulbecco's Modified Eagles Medium) enriched with 5% fetal calfserum and L-glutamine (4 mM final) in an incubator at 37° C. and with aCO₂ concentration of 5%.

At the end of the incubation, the amount of PGE₂ and PGF_(2α), producedand released into the supernatant were assayed using an EIA kit(produced and sold by Cayman Chemicals, Ann Arbor, Mich., USA).

The comparative compound used was indomethacin at a concentration of 10nM (Sigma-Aldrich), which is a non-steroidal anti-inflammatory drug thatinhibits in equal measure both PGE₂ and PGF_(2α).

The results, expressed as a percentage of inhibition of the productionof PGE₂ and of PGF_(2α) at a concentration of 10 μm, are given in Table2, in which “ia” (inactive) indicates an inhibitory activity of lessthan 20%.

TABLE 2 % inhibition at 10 μm Compound PGE₂ PGF_(2α) 1 63 ia 2 76 ia 391 34 4 72 ia 5 91 36 6 82 ia 7 90 39 9 100 ia 10 76 ia 12 75 ia 13 10036 16 74 ia 18 66 ia 19 87 43 20 75 ia 21 66 ia 22 79 ia 24 79 ia 25 89ia 28 65 ia 29 91 ia 30 75 ia Indomethacin 100 100  (10 nM)

For illustrative purposes, Table 3 collates the pIC₅₀ values of a numberof compounds of the invention, where pIC₅₀ represents the negativelogarithm of the IC₅₀, which, in turn, represents the concentration ofcompound that inhibits the production of PGE₂ or PGF_(2α) by 50%relative to cells that are stimulated but not treated with the samecompound.

In Table 3, “nd” means not determinable.

TABLE 3 pIC₅₀ Compound PGE₂ PGF_(2α) 2 5.7 nd 6 5.8 nd 9 5.9 4.3 10 5.7<4 13 6.1 nd 18 5.6 nd 19 6.0 4 20 5.5 <4 indomethacin 8.3 8.6

EXAMPLE 4 In Vivo Biological Activity

The test compound was evaluated in the model of acetic acid-inducedstretching in mice (Stock J. L. et al., J Clin Inv 2001, 107: 325-331).This test makes it possible to evaluate the antinociceptive activity ofthe compounds of the invention in a model of inflammatory pain.

Female CD-1 mice weighing 25-30 g were used for the test. The animalswere treated intraperitoneally with the test compound (0.1-10 mg/kg)suspended in methylcellulose (MTC). The control animals were treatedwith the vehicle alone (MTC) via the same route.

30 minutes after the treatment, the animals received an intraperitonealinjection of acetic acid (0.7 v/v in physiological solution, 16 μl/g ofbody weight) in order to induce inflammatory pain and to check theeffects of the test compound on the nociceptive response.

Immediately after the administration of acetic acid and for thefollowing 20 minutes, the number of stretches, which represents theparameter for evaluation of the nociceptive response, was measured.

As reported in Table 4, the compound of the invention induced, in adose-dependent manner, a reduction in stretching in the 20 minutesfollowing the administration of acetic acid, compared with the animalstreated with MTC alone.

TABLE 4 Treatment dose (mg/kg) No. of stretches % inhibition Vehicle —52 — Compound 2 0.1 38 27 1 36 31 10 25 52

EXAMPLE 5 Selectivity Between Isoforms of PGES

The test used makes it possible to evaluate the capacity of thecompounds of the invention to inhibit the production of PGE₂ in a humanlymphoma cell line U-937 that preferentially expresses an enzymaticisoform (cPGES), which is responsible for the production of PGE₂ underbasal conditions, in the absence of pro-inflammatory stimuli. Thisenzymatic form is different from the one predominantly expressed in theA549 cells (mPGES-1) after a pro-inflammatory stimulus.

The absence of inhibitory activity on PGE₂ in this cell model ensuresthe selectivity of the compound compared with the enzymatic formresponsible for the production of PGE₂ in the presence of inflammatorystimuli.

The results, expressed as a percentage of inhibition of the productionof PGE₂, are given in Table 5, in which “ia” (inactive) indicates aninhibitory activity of less than 20%. The reference compound used wasindomethacin at a concentration of 10 nM.

The compounds of the invention were found not to significantly inhibitthe production of PGE₂ owing mainly to the action of cPGES.

TABLE 5 % inhibition at 10 μM Compound PGE₂ 2 ia 6 ia 9 ia 10 22 13 3018 ia 19 ia 20 ia Indomethacin (10 nM) 78

1. A 2-arylindole compound substituted in position 5, of formula (I):

in which: X is a halogen atom or a (C₁-C₃)alkyl, trifluoromethyl, nitro,amino, cyano, di(C₁-C₃)alkylamino, hydroxy, (C₁-C₃)alkoxy, phenyl or(C₁-C₃)alkylphenyl group; Y and Z, which may be the same or different,are an H or halogen atom, or a (C₁-C₃)alkyl, trifluoromethyl, nitro,amino, di(C₁-C₃)alkylamino, hydroxy, (C₁-C₃)alkoxy, phenyl, COOH,(C₁-C₃)alkyl-COOH, (C₂-C₃)alkenyl-COOH, COOR, CONH₂, SO₂CH₃, SO₂NHCH₃ orNHSO₂CH₃ group; W is an O atom or a CH₂ or NH group; R is a hydrogenatom or a (C₁-C₆)alkyl or (C₃-C₇)cycloalkyl group optionally substitutedwith 1 to 3 hydroxy groups; R′ is an H atom or a (C₁-C₆)alkyl or(C₃-C₇)cycloalkyl group optionally substituted with 1 to 3 hydroxygroups; A is a phenyl, naphthyl or pyridine group optionally substitutedwith 1 to 3 substituents, which may be the same or different, selectedfrom halogen, (C₁-C₆)alkyl optionally substituted with 1 to 3 hydroxygroups, trifluoromethyl, nitro, amino, di(C₁-C₃)alkylamino, hydroxy,(C₁-C₃)alkoxy, benzyloxy, COOH, COOR, SO₂CH₃, SO₂NHCH₃, NHSO₂CH₃,POR₁R₂, OPOR₁R₂, (C₁-C₆)alkyl-COOH, (C₂-C₆)alkenyl-COOH, phenyl and(C₁-C₃)alkylphenyl, in which, in turn, R₁ and R₂, which may be the sameor different, are (C₁-C₃)alkyl; and the physiologically acceptableaddition salts, stereoisomers, enantiomers, hydrates, solvates andpolymorphic forms thereof.
 2. A compound according to claim 1,characterized in that X is halogen, (C₁-C₃)alkyl, trifluoromethyl, nitroor (C₁-C₃)alkoxy.
 3. A compound according to claim 2, characterized inthat X is Cl, Br, F, trifluoromethyl or nitro.
 4. A compound accordingto claim 1, characterized in that Y and Z are, independently of eachother, H, halogen, nitro, COOH, (C₁-C₃)alkyl, trifluoromethyl or(C₁-C₃)alkoxy.
 5. A compound according to claim 4, characterized in thatY and Z are, independently of each other, Cl, Br, F, trifluoromethyl,nitro, COOH, methyl, ethyl, methoxy or ethoxy.
 6. A compound accordingto claim 1, characterized in that R is methyl, ethyl, propyl, isopropylor cyclohexyl.
 7. A compound according to claim 1, characterized in thatR′ is H, methyl, ethyl, propyl, isopropyl or cyclohexyl.
 8. A compoundaccording to claim 1, characterized in that A is phenyl, naphthyl orpyridine optionally substituted with 1 or 2 substituents, which may bethe same or different, selected from halogen, (C₁-C₃)alkyl,(C₁-C₃)alkoxy and benzyloxy.
 9. A compound according to claim 8,characterized in that A is phenyl optionally substituted with 1 or 2substituents, which may be the same or different, selected from Br, Cl,F, methyl, ethyl, methoxy, ethoxy and benzyloxy.
 10. A compoundaccording to claim 8, characterized in that A is naphthyl optionallysubstituted with 1 or 2 substituents, which may be the same ordifferent, selected from Br, Cl, F, methyl, ethyl, methoxy, ethoxy andbenzyloxy.
 11. A compound according to claim 8, characterized in that Ais pyridine optionally substituted with 1 or 2 substituents, which maybe identical or different, selected from Br, Cl, F, methyl, ethyl,methoxy, ethoxy and benzyloxy.
 12. A process for preparing a2-arylindole compound substituted in position 5, of formula (I):

in which: X is a halogen atom or a (C₁-C₃)alkyl, trifluoromethyl, nitro,amino, cyano, di(C₁-C₃)alkylamino, hydroxy, (C₁-C₃)alkoxy, phenyl or(C₁-C₃)alkylphenyl group; Y and Z, which may be identical or different,are an H or halogen atom, or a (C₁-C₃)alkyl, trifluoromethyl, nitro,amino, di(C₁-C₃)alkylamino, hydroxy, (C₁-C₃)alkoxy, phenyl, COOH,(C₁-C₃)alkyl-COOH, (C₂-C₃)alkenyl-COOH, COOR, CONH₂, SO₂CH₃, SO₂NHCH₃ orNHSO₂CH₃ group; W is an O atom or a CH₂ or NH group; R is a hydrogenatom or a (C₁-C₆)alkyl or (C₃-C₇)cycloalkyl group optionally substitutedwith 1 to 3 hydroxy groups; R′ is an H atom or a (C₁-C₆)alkyl or(C₃-C₇)cycloalkyl group optionally substituted with 1 to 3 hydroxygroups; A is a phenyl, naphthyl or pyridine group optionally substitutedwith 1 to 3 substituents, which may be identical or different, selectedfrom halogen, (C₁-C₆)alkyl optionally substituted with 1 to 3 hydroxygroups, trifluoromethyl, nitro, amino, di(C₁-C₃)alkylamino, hydroxy,(C₁-C₃)alkoxy, benzyloxy, COOH, COOR, SO₂CH₃, SO₂NHCH₃, NHSO₂CH₃,POR₁R₂, OPOR₁R₂, (C₁-C₆)alkyl-COOH, (C₂-C₆)alkenyl-COOH, phenyl and(C₁-C₃)alkylphenyl, in which, in turn, R₁ and R₂, which may be identicalor different, are (C₁-C₃)alkyl; characterized in that: a) a compound offormula (II):

in which X, Y and Z have the meanings given above, and Q is a halogenatom or a hydroxy group, is reacted with a compound of formula (III):

in which R and R′ have the meanings given above, and G has the samemeanings as A or is a hydrogen atom, to give a compound of formula (IV):

in which X, Y, Z, W, G, R and R′ have the meanings given above, and b)when G is H, the compound of formula (IV) is reacted with a compound offormula (V):IA  (V) in which I is an iodine atom, and A has the meanings givenabove, to give the compound of formula (I), and c) if so desired, aphysiologically acceptable addition salt of the compound of formula (IV)from step (a) in which G is other than H or of the compound of formula(I) from step (b) is formed.
 13. A process according to claim 12,characterized in that step (a) is performed by reacting a compound offormula (II) in which Q is Cl with an amine of formula (III) in thepresence of a suitable acid acceptor according to standard techniques.14. A process according to claim 12, characterized in that step (a) isperformed by reacting a compound of formula (II) in which Q is OH withan amine of formula (III) in the presence of a suitable coupling agentaccording to standard techniques.
 15. An intermediate compound offormula (III):

in which R is a (C₁-C₆)alkyl or (C₃-C₇)cycloalkyl group optionallysubstituted with 1 to 3 hydroxy groups; R′ is an H atom or a(C₁-C₆)alkyl or (C₃-C₇)cycloalkyl group optionally substituted with 1 to3 hydroxy groups, G is a phenyl, naphthyl or pyridine group optionallysubstituted with 1 to 3 substituents, which may be identical ordifferent, selected from halogen, (C₁-C₆)alkyl optionally substitutedwith 1 to 3 hydroxy groups, trifluoromethyl, nitro, amino,di(C₁-C₃)alkylamino, hydroxy, (C₁-C₃)alkoxy, benzyloxy, COOH, COOR,SO₂CH₃, SO₂NHCH₃, NHSO₂CH₃, POR₁R₂, OPOR₁R₂, (C₁-C₆)alkyl-COOH,(C₂-C₆)alkenyl-COOH, phenyl and (C₁-C₃)alkylphenyl, in which, in turn,R₁ and R₂, which may be identical or different, are (C₁-C₃)alkyl;provided, however, that G is not an unsubstituted phenyl group when R ismethyl and R′ is H.
 16. An intermediate compound according to claim 15,characterized in that R is methyl, ethyl, propyl, isopropyl orcyclohexyl.
 17. An intermediate compound according to claim 15,characterized in that R′ is H, methyl, ethyl, propyl, isopropyl orcyclohexyl.
 18. A pharmaceutical composition containing an effectiveamount of a compound of formula (I):

in which: X is a halogen atom or a (C₁-C₃)alkyl, trifluoromethyl, nitro,amino, cyano, di(C₁-C₃)alkylamino, hydroxy, (C₁-C₃)alkoxy, phenyl or(C₁-C₃)alkylphenyl group; Y and Z, which may be identical or different,are an H or halogen atom, or a (C₁-C₃)alkyl, trifluoromethyl, nitro,amino, di(C₁-C₃)alkylamino, hydroxy, (C₁-C₃)alkoxy, phenyl, COOH,(C₁-C₃)alkyl-COOH, (C₂-C₃)alkenyl-COOH, COOR, CONH₂, SO₂CH₃, SO₂NHCH₃ orNHSO₂CH₃ group; W is an O atom or a CH₂ or NH group; R is a hydrogenatom or a (C₁-C₆)alkyl or (C₃-C₇)cycloalkyl group optionally substitutedwith 1 to 3 hydroxy groups; R′ is an H atom or a (C₁-C₆)alkyl or(C₃-C₇)cycloalkyl group optionally substituted with 1 to 3 hydroxygroups; A is a phenyl, naphthyl or pyridine group optionally substitutedwith 1 to 3 substituents, which may be identical or different, selectedfrom halogen, (C₁-C₆)alkyl optionally substituted with 1 to 3 hydroxygroups, trifluoromethyl, nitro, amino, di(C₁-C₃)alkylamino, hydroxy,(C₁-C₃)alkoxy, benzyloxy, COOH, COOR, SO₂CH₃, SO₂NHCH₃, NHSO₂CH₃,POR₁R₂, OPOR₁R₂, (C₁-C₆)alkyl-COOH, (C₂-C₆)alkenyl-COOH, phenyl and(C₁-C₃)alkylphenyl, in which, in turn, R₁ and R₂, which may be identicalor different, are (C₁-C₃)alkyl; or of a physiologically acceptableaddition salt, stereoisomer, enantiomer, hydrate, solvate or polymorphicform thereof, and at least one pharmaceutically acceptable inertingredient.